Immune system responses may be classified as humoral or cell-mediated. A humoral response is mediated by B lymphocytes in the form of freely diffusible antibody molecules. A cell-mediated response is mediated by specifically reactive lymphocytes, such as T lymphocytes ("T cells"), rather than antibodies.
T cells react with foreign antigens via surface receptors that are distinctive for each T cell clone. The T cell surface receptors are generally composed of two disulfide-linked protein chains having unique amino acid sequences (Edelson, R., "Photopheresis: A Clinically Relevant Immunobiologic Response Modifier", Annals of N.Y. Academy of Sciences 636:154-164 (1991). The physical properties of these receptors confer specific binding capabilities and permit each of the several million clones of T cells in an individual to operate independently.
The T cell receptor is capable of recognizing a particular antigen only when it is associated with a surface marker on an antigen presenting cell, such as a macrophage. The surface markers belong to a group of molecules known as the major histocompatibility complex (MHC). Binding of the T cell receptor to the antigen on the antigen presenting cell induces changes in the T cell, which changes collectively comprise the cell-mediated response.
The induction of expression of "empty", i.e., devoid of peptide, major histocompatibility complex class I molecules under conditions of reduced temperature has been demonstrated in a murine lymphoma mutant cell line (Ljunggren et al., Nature 336:476-480 (1990)). The mutant cell line lacks the appropriate intracellular mechanism for loading intracellular peptides into the binding clefts of newly synthesized class I molecules. The mutant cell line class I molecules are substantially empty and thermodynamically unstable at 37.degree. C., but are stabilized by providing an exogenous source of peptides which bind to the empty class I molecules. An increased level of major histocompatibility complex class I expression has also been reported for a corresponding wild-type cell line (ibid.) when grown at temperatures below 37.degree. C. However, the tests used to identify class I expression in that system did not distinguish between empty class I and class I molecules associated with peptide.
Improvement in the relatively inefficient exchanging of an exogenously added peptide for peptides already present in the clefts of class I molecules by the addition of exogenous free beta-2-microglobulin has also been demonstrated (Rock et al., PNAS (USA) 87:7517-7521 (1990).
Two signals are primarily responsible for inducing the T cell mediated response to an antigen presenting cell which is associated with antigen. A first signal is due to binding of the T cell to the antigen on the antigen presenting cell. A second, co-stimulatory signal is sent by "accessory" membrane molecules or soluble messengers from the antigen presenting cell to the responding T cell. These soluble intercellular messengers regulate the amplitude and duration of the immune response and are given the generic term, cytokines. Cytokines include the group previously referred to as lymphokines, monokines, interleukins and interferons (Essential Immunology, seventh edition, Blackwell Scientific Publications, Oxford, Great Britain, 1991, pp. 140-150). If the antigen presenting cell does not send the second signal, the T cell is effectively paralyzed, i.e., unable to mount an immune response to the antigen. Certain types of antigen presenting cells, e.g., resting T cells, are unable to send the second signal. Accordingly, in the absence of exogenous cytokine or other second signal, such resting T cells which function as antigen presenting cells down-regulate an immune response to the presented antigen and lead to antigen specific immunologic paralysis of the T cell whose membrane receptor has been engaged.
T cells also function in regulation of an immune response via recognition by the immune system of the T cell surface receptor. Thus, several studies, described herein, have suggested that the ability of the immune system to recognize the receptor of an aberrant T cell clone as antigenic makes possible the vaccination of a patient against a pathogenic clone of T cells.
Cutaneous T cell lymphoma (CTCL) is an example of an immune system disease that is caused by a massive expansion of a single clone of aberrant T cells. Extracorporeal photochemotherapy ("photopheresis") for the treatment of cutaneous T cell lymphoma has been described (Edelson, R., "Light-activated Drugs", Scientific American 256(8): 68-75 (1988); Edelson, R., "Photopheresis: A Clinically Relevant Immunobiologic Response Modifier", Annals of N.Y. Academy of Sciences 636:154-164 (1991). The treatment comprises isolating the patient's T cells, irradiating the cells in the presence of a photoactivatable agent (8-MOP) and reinfusing the damaged T cells. The 8-MOP is activated by the ultraviolet light to form a transient molecule capable of photomodifying cellular DNA. This therapy reportedly results in selective destruction of the malignant T cell clone.
It is believed that exposure of the malignant clone to 8-MOP and ultraviolet light, followed by return of the irradiated, damaged cells to the patient, elicits a specific response to the aberrant T cells that is mediated by T cell surface receptors, i.e., the damaged cells of the malignant clone had, in effect, primed the immune system to specifically destroy the clone. In essence, photopheresis "vaccinated" the CTCL patients against their own cancer.
Photopheresis has also been used for the treatment of several autoimmune disorders, including pemphigus vulgaris and systemic sclerosis (Rook, A., "Photopheresis in the Treatment of Autoimmune Disease: Experience with Pemphigus Vulgaris and Systemic Sclerosis", Annals of N.Y. Academy of Science 636:209-216 (1991) and rheumatoid arthritis (Malawista, S., et al., "Photopheresis for Rheumatoid Arthritis", Annals of N.Y. Academy of Science 636:217-226 (1991).
U.S. Pat. No. 4,838,852, issued to Edelson et al. (hereinafter Edelson '852), the contents of which are incorporated herein by reference, describes a method for altering the immune system response of a mammal to an antigen. The Edelson '852 method comprises (a) contacting the subject's immune system with the specific antigen for a suitable time to artificially stimulate the immune system, (b) withdrawing antigen-stimulated blood cell material from the subject, (c) treating the withdrawn material to alter the antigen-stimulated cells, and (d) returning the treated material to the subject. Contacting the subject's immune system with the specific antigen is achieved in any manner which introduces the antigen into the mammal's immune system, e.g., by injecting directly into the blood stream, the lymphatic system or the lymphoid organs. Edelson '852 also discloses that it may be possible to render the cells incapable of recognizing an antigen by withdrawing the blood cell containing material from the subject, treating the withdrawn material as above, returning the treated material to the subject and then contacting the subject's immune system with a specific antigen.
U.S. Pat. No. 5,147,289, issued to Edelson (hereinafter Edelson '289), the contents of which are incorporated hereinby reference, describes methods for non-specifically enhancing the immune system response of a mammal to an antigen. The method comprises (A) enhancing the immune system response by (a) withdrawing leukocyte containing material from the mammal, (b) treating the withdrawn leukocytes in a manner to alter the cells, (c) returning the treated leukocytes to the mammal and (B) artificially contacting the mammal's immune system with the antigen for a suitable period of time to stimulate an immune system response.
With respect to the Edelson '852 and '289 patents, the withdrawn leukocytes may be altered by, for example, inactivating the cells by photopheresis, exposing the cells to high or low temperature, high or low pH values, high or low pressure, hypotonic solutions, chemotherapeutic agents, or a variety of other inactivating conditions.
Photopheresis also has been used prophylactically to prevent graft rejection by injecting into mice a preparation containing Photoinactivated Effector T ("PET") cells (Perez, M. et al., "Inhibition of Antiskin Allograft Immunity Induced by Infusions with Photoinactivated Effector T Lymphocytes (PET Cells); "The Congenic Model", Transplantation 51:1283-1289 (1991). To prepare the PET cells, T cell clones mediating skin graft rejection were expanded in vivo and photoinactivated using 8-MOP. Perez et al. report that this procedure results in the adoptive transfer of tolerance for skin allotransplantation, as demonstrated by prolongation of allograft survival in the recipients of PET cells.
A preliminary study to evaluate the potential therapeutic value of photopheresis in seven patients with AIDS-related complex (ARC) has been reported (Bisaccia, E. et al., "Viral-Specific Immunization in AIDS-Related Complex by Photopheresis", Annals of N.Y. Academy of Science 636:321-330 (1991). One advantage of photopheresis for the treatment of an immunocompromised patient, such as an AIDS patient, is that unlike antiviral drug treatments, extracorporeal photopheresis spares the tissue-fixed elements of the immune system from exposure to the therapy, thereby minimizing damage to the antigen processing system.
Photopheresis has been demonstrated to produce a generalized clinical benefit for a variety of autoimmune diseases that are characterized by a disorder in T cell regulation. In addition to producing an immunization effect against clones of autoreactive T cells, photopheresis may also result in induction of soluble extracellular messengers, e.g., tumor necrosis factor, which have a therapeutic adjuvant effect for a number of disease states.
The above-described therapies have in common the ability to vaccinate against a particular T cell activity without isolating or identifying the clone(s) responsible for the activity. None of the cited references and/or patents disclose a method for specifically regulating an immune system response. Accordingly, there is still a need for methods and pharmaceutical compositions to precisely regulate the immune system response to a specific antigen. Such methods would permit stimulation of a competent or incompetent immune system and would permit the stimulation of an immune system in a subject already weakly stimulated with the antigen. Preferably, such methods and compositions would permit stimulation of the immune system in the form of booster immunizations.